Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| St. |
RCV000761030 | SCV000890945 | uncertain significance | Neuroblastoma, susceptibility to, 2 | 2020-12-16 | criteria provided, single submitter | clinical testing | The PHOX2B c.556G>A (p.Glu186Lys) missense change is absent in gnomAD v2.1.1 (PM2_Supporting). In silico tools predict a benign effect on the gene or protein function (BP4), however to our knowledge these predictions have not been confirmed by functional studies. This variant has not been identified in individuals with familial neuroblastoma. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. |
| Ambry Genetics | RCV002343612 | SCV002650910 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-05-16 | criteria provided, single submitter | clinical testing | The p.E186K variant (also known as c.556G>A), located in coding exon 3 of the PHOX2B gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003633542 | SCV004512996 | uncertain significance | Haddad syndrome | 2023-07-03 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. ClinVar contains an entry for this variant (Variation ID: 620600). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the PHOX2B protein (p.Glu186Lys). |